Methamphetamine (MA) dependence is a major public health concern; however, a widely accepted pharmacotherapy has not yet been identified. The results of several clinical trials indicate that d-amphetamine, a medication that shares neurochemical, behavioral and pharmacological effects with MA, reduces street use of stimulants and severity of withdrawal in amphetamine-dependent patients. Unfortunately, clinicians may not favor d-amphetamine, because of its high abuse potential. Indeed, d-amphetamine is reportedly abused, primarily by crushing the tablets in order to snort the drug. It is likely then, the potential for the clinical utility of d- amphetamine may be enhanced by the development of abuse-deterrent formulations, that are resistant to tampering to extract the active stimulant. One such product, lisdexamfetamine (LDX) is the first FDA-approved pro-drug stimulant, that is a therapeutically inactive molecule. After oral ingestion, however, it is converted to d-amphetamine, which is responsible for the drug's activity. A recent study of abuse liability showed that at doses of LDX and d- amphetamine that contain equivalent molar amounts of free amphetamine base, LDX produced significantly less drug liking than did d-amphetamine. This finding suggests that LDX has low stimulant properties, and little abuse potential, highlighting its suitability as a candidate medication for MA dependence. However, the safety of administering LDX with MA, and the ability of LDX to modify the abuse-related behavioral effects of MA have yet to be tested. We propose to conduct human laboratory evaluations of the safety and initial efficacy of LDX as a pharmacotherapy for MA dependence. The first specific aim is to evaluate the safety and tolerability of administering LDX in combination with intravenous MA in humans. MA-dependent individuals will receive ascending doses of intravenous (i.v.) MA while maintained on increasing doses of LDX (Exp. 1). Cardiovascular indices will be used to determine the safety of the LDX-MA combinations while subjective measures will be used to characterize the behavioral effects. The results of this experiment will guide the selection of the dose to be tested in Exp.2. The second specific aim is to determine whether LDX maintenance attenuates the reinforcing effects of MA. To accomplish this aim, we will assess MA self-administration, during LDX maintenance, in a progressive-ratio schedule of reinforcement (Exp. 2). The reinforcing effects of drugs, including MA, are central to their abuse potential. An effective pharmacotherapy for stimulant dependence should reduce MA self-administration. If successful, the findings from the proposed study will provide crucial scientific information on the safety and initial efficacy of LDX that could be useful for larger clinical trials evaluating efficacy of LDX for MA dependence. The results of this study will also help elucidate the optimal conditions (e.g., dose) under which LDX might be expected to be effective. PUBLIC HEALTH RELEVANCE: The proposal offers to provide important scientific and clinical information on the safety and initial efficacy of lisdexamfetamine (LDX) as a putative pharmacotherapy for methamphetamine (MA) dependence. The proposed human laboratory research will elucidate the optimal conditions (e.g., dose) under which LDX might be expected to be safe and effective. Because a widely accepted medication for treating MA dependence is not yet available, and the cost associated with clinical trials is substantial, human laboratory research can provide an economical and efficient approach for determining preliminary efficacy of LDX for MA dependence.